Metastasis—the process in which cancer cells spread, or disseminate, from the primary tumor to form tumors in other organs of the body—is the leading cause of cancer-related deaths. Strategies are urgently needed for keeping disseminated tumor cells in a latent state so they can’t cause metastases.
In 2015, Julio Aguirre-Ghiso, Ph.D., and his team identified the receptor NR2F1, present in the nuclei of tumor cells, as a master regulator of tumor cell dormancy. Now, as described in a study published online November 23 in the Journal of Experimental Medicine, he and his colleagues have discovered a compound that activates this nuclear receptor and have shown it can cause tumor-cell dormancy in cancer cell lines and in a patient-derived mouse model of metastatic cancer. The investigation was a collaboration with the laboratory of Soledad Sosa, Ph.D., at the Mount Sinai Tisch Cancer Institute, the first author on the 2015 study.
The researchers screened 110,000 drug-like compounds to find NR2F1 agonists, i.e., compounds whose molecular structures enable them to activate NR2F1 in cancer cells and cause them to become dormant. One compound in particular, dubbed C26, stood out for its ability to consistently and significantly activate NR2F1 and was chosen for further testing.
When two different head-and-neck cancer cell lines were treated with C26, the cells were no longer able to multiply. The same result occurred when cancer cells from a head-and-neck cancer patient were used to create a patient-derived xenograft (PDX) tumor in an immunodeficient mouse. In addition, C26 induced dormancy in tumor cells derived directly after surgery from patients with head-and-neck cancer.
Most impressive of all were experiments assessing whether C26-mediated activation of NR2F1 could inhibit metastasis. Mice were injected subcutaneously with cells from a highly aggressive head-and-neck cancer PDX known to cause metastases in the lung. The animals were then treated for 5 days with either C26 or a control compound before surgery to remove the primary tumor, and the mice were then treated for an additional four weeks. Thirty-three percent of control mice had small metastases in their lungs and 50% had both small and large lung metastases. By contrast, no metastases were found in any of the C26-treated mice. Only dormant solitary cancer cells were found in the C26-treated mice, and those cells persisted in a dormant state even if C26 treatment was stopped.
The results support the use of C26 or other NR2F1 agonists as a therapeutic strategy for inducing cancer-cell dormancy and suppressing metastatic disease. The authors note that these agonists could be especially useful for treating patients at risk for developing initial metastases or for targeting residual cancer cells after metastatic lesions have been successfully removed.
Dr. Aguirre-Ghiso is director of the Institute for Cancer Dormancy and Tumor Microenvironment at the Albert Einstein Cancer Center and an Endowed Professor of cell biology at Einstein.
Posted on: Tuesday, November 23, 2021